Certain 2,6-diisopropyl-4-(4-fluoro-phenyl)-3,5-bis-dimethyl-3&#39;,5&#39;-dihydroxy-hept-6-enoate-pyridine derivatives useful for treating lipoproteinaemia and arteriosclerosis

ABSTRACT

For the treatment of lipoproteinaemia and arteriosclerosis, the new disubstituted pyridines of the formula ##STR1## in which R 1  is optionally substituted aryl or heteroaryl, 
     R 2  is cycloalkyl or optionally substituted alkyl, 
     R 3  is hydrogen, cycloalkyl, or optionally substituted alkyl, aryl or heteroaryl, 
     X is --CH 2  --CH 2  -- or --CH═CH--, 
     A is ##STR2## R 6  is hydrogen or alkyl, and R 7  is hydrogen, alkyl, aralkyl or a cation.

The invention relates to disubstituted pyridines, intermediates fortheir preparation, and their preparation and their use in medicaments.

It has been disclosed that lactone derivatives isolated from fungalcultures are inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme Areductase (HMG-CoA reductase) [mevinolin, EP-A No. 22,478; U.S. Pat. No.4,231,938]. Moreover, certain indole derivatives or pyrazole derivativesare also inhibitors of HMG-CoA reductase [EP-A No. 1,114,027; U.S. No.4,613,610].

Disubstituted pyridines of the general formula (I) ##STR3## in whichR¹ - denotes heteroaryl which can be monosubstituted, disubstituted ortrisubstituted by identical or different halogen, alkyl, alkoxy,alkylthio, alkylsulphonyl, aryl, aryloxy, arylthio, arylsulphonyl,trifluoromethyl, trifluoromethoxy, trifluoromethylthio oralkoxycarbonyl, or by a group of the formula --NR⁴ R₅, wherein

R⁴ and R⁵ - are identical or different and denote alkyl, aryl, aralkyl,acyl, alkylsulphonyl or arylsulphonyl,

or

- denotes aryl which can be monosubstituted to pentasubstituted byidentical or different alkyl, alkoxy, alkylthio, alkylsulphonyl, aryl,aryloxy, arylthio, arylsulphonyl, aralkyl, aralkoxy, aralkylthio,aralkylsulphonyl, halogen, cyano, nitro, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulphamoyl,dialkylsulphamoyl, carbamoyl or dialkylcarbamoyl, or by a group of theformula --NR⁴ R⁵, wherein

R⁴ and R⁵ have the abovementioned meaning,

R² - denotes cycloalkyl, or

- denotes alkyl which can be substituted by halogen, cyano, alkoxy,alkylthio, alkylsulphonyl, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, trifluoromethylsulphonyl, alkoxycarbonyl or acyl,or by a group of the formula --NR⁴ R⁵, wherein

R⁴ and R⁵ have the abovementioned meaning, or by carbamoyl,dialkylcarbamoyl, sulphamoyl, dialkylsulphamoyl, heteroaryl, aryl,aryloxy, arylthio, arylsulphonyl, aralkoxy, aralkylthio oraralkylsulphonyl, where the heteroaryl and aryl radicals of thelast-mentioned substituents can be monosubstituted, disubstituted ortrisubstituted by identical or different halogen, cyano,trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio oralkylsulphonyl,

R³ - denotes hydrogen, or

- denotes cycloalkyl, or

- denotes alkyl which can be substituted by halogen, cyano, alkoxy,alkylthio, alkylsulphonyl, trifluoromethyl, trifluoromethoxy,trifluomethylthio, trifluoromethylsulphonyl, alkoxycarbonyl or acyl, orby a group of the formula --NR⁴ R⁵, wherein

R⁴ and R⁵ have the abovementioned meaning, or by carbamoyl,dialkylcarbamoyl, sulphamoyl, dialkylsulphamoyl, heteroaryl, aryl,aryloxy, arylthio, arylsulphonyl, aralkoxy, aralkylthio oraralkylsulphonyl, where the heteroaryl and aryl radicals can bemonosubstituted, disubstituted or trisubstituted by identical ordifferent halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl,alkoxy, alkylthio or alkylsulphonyl, or

- denotes heteroaryl which can be monosubstituted, disubstituted ortrisubstituted by identical or different halogen, alkyl, alkoxy,alkylthio, alkylsulphonyl, aryl, aryloxy, arylthio, arylsulphonyl,trifluoromethyl, trifluoromethoxy, trifluoromethylthio oralkoxycarbonyl, or by a group of the formula --NR⁴ R⁵, wherein

R⁴ and R⁵ have the abovementioned meaning, or

- denotes aryl which can be monosubstituted to pentasubstituted byidentical or different alkyl, alkoxy, alkylthio, alkylsulphonyl, aryl,aryloxy, arylthio, arylsulphonyl, aralkyl, aralkoxy, aralkylthio,aralkylsulphonyl, halogen, cyano, nitro, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulphamoyl,dialkylsulphamoyl, carbamoyl or dialkylcarbamoyl, or by a group of theformula --NR⁴ R⁵, wherein

R⁴ and R⁵ have the abovementioned meaning,

X - denotes a group of the formula --CH₂ --CH₂ -- or --CH═CH--, and

A - denotes a group of the formula ##STR4## wherein R⁶ - stands forhydrogen or alkyl and

R⁷ - stands for hydrogen or

- stands for alkyl, aryl or aralkyl or

- stands for a cation,

have now been found.

Surprisingly, the disubstituted pyridines according to the inventionshow a superior inhibitory action on HMG-CoA reductase(3-hydroxy-3-methyl-glutaryl coenzyme A reductase).

Cycloalkyl in general stands for a cyclic hydrocarbon radical having 3to 8 carbon atoms. The cyclopropane, cyclopentane and the cyclohexanering is preferred. Examples which may be mentioned are cyclopropyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Alkyl in general stands for a straight-chain or branched hydrocarbonradical having 1 to 12 carbon atoms. Lower alkyl having 1 to about 6carbon atoms is preferred. Examples which may be mentioned are methyl,ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl,isohexyl, heptyl, isoheptyl, octyl and isooctyl.

Alkoxy in general stands for a straight-chain or branched hydrocarbonradical having 1 to 12 carbon atoms which is bonded via an oxygen atom.Lower alkoxy having 1 to about 6 carbon atoms is preferred. An alkoxyradical having 1 to 4 carbon atoms is particularly preferred. Exampleswhich may be mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy,octoxy

Alkylthio in general stands for a straight-chain or branched hydrocarbonradical having 1 to 12 carbon atoms which is bonded via a sulphur atom.Lower alkylthio having 1 to about 6 carbon atoms is preferred. Analkylthio radical having 1 to 4 carbon atoms is particularly preferred.Examples which may be mentioned are methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, pentylthio, isopentylthio,hexylthio, isohexylthio, heptylthio, isoheptylthio, octylthio andisooctylthio.

Alkylsulphonyl in general stands for a straight-chain or branchedhydrocarbon radical having 1 to 12 carbon atoms which is bonded via anSO₂ group. Lower alkylsulphonyl having 1 to about 6 carbon atoms ispreferred. Examples which may be mentioned are: methylsulphonyl,ethylsulphonyl, propylsulphonyl, isopropylsulphonyl, butylsulphonyl,isobutylsulphonyl, pentylsulphonyl, isopentylsulphonyl, hexylsulphonyland isohexylsulphonyl.

Sulphamoyl (aminosulphonyl) stands for the group --SO₂ --NH₂.

Aryl in general stands for an aromatic radical having 6 to about 12carbon atoms. Preferred aryl radicals are phenyl, naphthyl and biphenyl.

Aryloxy in general stands for an aromatic radical having 6 to about 12carbon atoms which is bonded via an oxygen atom. Preferred aryloxyradicals are phenoxy and naphthyloxy.

Arylthio in general stands for an aromatic radical having 6 to about 12carbon atoms which is bonded via a sulphur atom. Preferred arylthioradicals are phenylthio and naphthylthio.

Arylsulphonyl in general stands for an aromatic radical having 6 toabout 12 carbon atoms which is bonded via an SO₂ group. Examples whichmay be mentioned are phenylsulphonyl, naphthylsulphonyl andbiphenylsulphonyl.

Aralkyl in general stands for an aryl radical having 7 to 14 carbonatoms which is bonded via an alkylene chain. Aralkyl radicals having 1to 6 carbon atoms in the aliphatic moiety and 6 to 12 carbon atoms inthe aromatic moiety are preferred. Examples which may be mentioned arethe following aralkyl radicals: benzyl, naphthylmethyl, phenethyl andphenylpropyl.

Aralkoxy in general stands for an aralkyl radical having 7 to 14 carbonatoms, the alkylene chain being bonded via an oxygen atom. Aralkoxyradicals having 1 to 6 carbon atoms in the aliphatic moiety and 6 to 12carbon atoms in the aromatic moiety are preferred. Examples which may bementioned are the following aralkoxy radicals: benzyloxy,naphthylmethoxy, phenethoxy and phenylpropoxy.

Aralkylthio in general stands for an aralkyl radical having 7 to about14 carbon atoms, the alkyl chain being bonded via a sulphur atom.Aralkylthio radicals having 1 to 6 carbon atoms in the aliphatic moietyand 6 to 12 carbon atoms in the aromatic moiety are preferred. Exampleswhich may be mentioned are the following aralkylthio radicals:benzylthio, naphthylmethylthio, phenethylthio and phenylpropylthio.

Aralkylsulphonyl in general stands for an aralkyl radical having 7 toabout 14 carbon atoms, the alkyl radical being bonded via an SO₂ link.Aralkylsulphonyl radicals having 1 to 6 carbon atoms in the aliphaticmoiety and 6 to 12 carbon atoms in the aromatic moiety are preferred.Examples which may be mentioned are the following aralkylsulphonylradicals: benzylsulphonyl, naphthylmethylsulphonyl, phenethylsulphonyland phenylpropylsulphonyl.

Alkoxycarbonyl can be represented, for example, by the formula ##STR5##In this connection, alkyl stands for a straight-chain or branchedhydrocarbon radical having 1 to 12 carbon atoms. Lower alkoxycarbonylhaving 1 to about 6 carbon atoms in the alkyl moiety is preferred. Analkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety isparticularly preferred. Examples which may be mentioned are thefollowing alkoxycarbonyl radicals: methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl andisobutoxycarbonyl.

Acyl in general stands for phenyl or straight-chain or branched loweralkyl having 1 to about 6 carbon atoms which are bonded via a carbonylgroup. Phenyl and alkyl radicals having up to 4 carbon atoms arepreferred. Examples which may be mentioned are benzoyl, acetyl,ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl andisobutylcarbonyl.

Halogen in general stands for fluorine, chlorine, bromine or iodine,preferably for fluorine, chlorine or bromine. Particularly preferably,halogen stands for fluorine or chlorine.

Heteroaryl in general stands for a 5- to 6-membered aromatic ring whichcan contain oxygen, sulphur and/or nitrogen as hetero atoms and ontowhich can be fused further aromatic rings. 5- and 6-membered aromaticrings which contain one oxygen, one sulphur and/or up to 2 nitrogenatoms and which are optionally fused to benzene are preferred.Heteroaryl radicals which may be mentioned as particularly preferred arethienyl, furyl, pyrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl,phthalazinyl, cinnolyl, thiazolyl, benzothiazolyl, isothiazolyl,oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzimidazolyl, indolyland isoindolyl.

In the context of the present invention, disubstituted pyridines (Ia)correspond to the general formula ##STR6## in which R¹, R², R³, X and Ahave the abovementioned meaning.

In the context of the present invention, disubstituted pyridines (Ib)correspond to the general formula ##STR7## in which R¹, R², R³, X and Ahave the abovementioned meaning.

In the context of the general formula (I), compounds having the generalformulae (Ia) and (Ib) are preferred.

Preferred compounds are those of the general formula (Ia) and (Ib)##STR8## in which R¹ - denotes thienyl, furyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl,quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl orbenzimidazolyl, each of which can be monosubstituted or disubstituted byidentical or different fluorine, chlorine, bromine, lower alkyl, loweralkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or loweralkoxycarbonyl, or

- denotes phenyl or naphthyl, each of which can be monosubstituted totetrasubstituted by identical or different lower alkyl, lower alkoxy,lower alkylthio, lower alkylsulphonyl, phenyl, phenyloxy, phenylthio,phenylsulphonyl, benzyl, benzyloxy, benzylthio, benzylsulphonyl,phenethyl, phenylethoxy, phenylethylthio, phenylethylsulphonyl,fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy,trifluoromethylthio or lower alkoxycarbonyl, or by a group of theformula --NR⁴ R⁵, where

R⁴ and R⁵ are identical or different and denote lower alkyl, phenyl,benzyl, acetyl, benzoyl, phenylsulphonyl or lower alkylsulphonyl,

R² - denotes cyclopropyl, cyclopentyl or cyclohexyl, or

- denotes lower alkyl which can be substituted by fluorine, chlorine,bromine, cyano, lower alkoxy, lower alkylthio, lower alkylsulphonyl,phenyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulphonyl,lower alkoxycarbonyl, benzoyl or lower alkylcarbonyl, or by a group ofthe formula --NR⁴ R⁵, wherein

R⁴ and R⁵ have the abovementioned meaning, or by pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl,thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy,phenylthio, phenylsulphonyl, benzyloxy, benzylthio, benzylsulphonyl,phenylethoxy, phenylethylthio or phenylethylsulphonyl, where theheteroaryl and aryl radicals mentioned can be monosubstituted ordisubstituted by identical or different fluorine, chlorine, bromine,lower alkyl, lower alkoxy, trifluoromethyl or trifluoromethoxy,

R³ - denotes hydrogen, or

- cyclopropyl, cyclopentyl or cyclohexyl, or

- denotes lower alkyl which can be substituted by fluorine, chlorine,bromine, cyano, lower alkoxy, lower alkylthio, lower alkylsulphonyl,trifluoromethyl, trifluoromethoxy, trifluoromethylsulphonyl, loweralkoxycarbonyl, benzoyl or lower alkylcarbonyl, or by a group of theformula --NR⁴ R⁵, wherein

R⁵ and R⁶ have the abovementioned meaning, or by pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl,thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy,phenylthio, phenylsulphonyl, benzyloxy, benzylthio, benzylsulphonyl,phenylethoxy, phenylethylthio or phenylethylsulphonyl, where theheteroaryl and aryl radicals mentioned can be monosubstituted ordisubstituted by identical or different fluorine, chlorine, bromine,lower alkyl, lower alkoxy, trifluoromethyl or trifluoromethoxy,

- denotes thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl,quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl,cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, each ofwhich can be monosubstituted or disubstituted by identical or differentfluorine, chlorine, bromine, lower alkyl, lower alkoxy, phenyl, phenoxy,trifluoromethyl, trifluoromethoxy or lower alkoxycarbonyl, or

- denotes phenyl or naphthyl, each of which can be monosubstituted totetrasubstituted by identical or different lower alkyl, lower alkoxy,lower alkylthio, lower alkylsulphonyl, phenyl, phenyloxy, phenylthio,phenylsulphonyl, benzyl, benzyloxy, benzylthio, benzylsulphonyl,phenethyl, phenylethoxy, phenylethylthio, phenylethylsulphonyl,fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy,trifluoromethylthio or lower alkoxycarbonyl, or by a group of theformula --NR⁵ R⁶, where

R⁵ and R⁶ have the abovementioned meaning,

X - denotes a group of the formula --CH═CH-- and

A - denotes a group of the formula ##STR9## wherein R⁶ - denoteshydrogen or lower alkyl, and

R⁷ - denotes lower alkyl, phenyl or benzyl, or

- denotes a physiologically tolerable cation.

Particularly preferred compounds are those of the general formula (Ia)and (Ib) in which

R¹ - denotes pyridyl, pyrimidyl, quinolyl or isoquinolyl, each of whichcan be substituted by fluorine, chlorine, methyl, methoxy ortrifluoromethyl, or

- denotes phenyl which can be monosubstituted, disubstituted ortrisubstituted by identical or different methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert.butyl, methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, tert.butoxy, methylthio, ethylthio,propylthio, isopropylthio, methylsulphonyl, ethylsulphonyl,propylsulphonyl, isopropylsulphonyl, phenyl, phenoxy, benzyl, benzyloxy,fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl or tert.butoxycarbonyl,

R² - denotes cyclopropyl, cyclopentyl or cyclohexyl, or

- denotes methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl ortert.butyl, each of which can be substituted by fluorine, chlorine,bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy,sec.butoxy, tert.butoxy, methylthio, ethylthio, propylthio,isopropylthio, methylsulphonyl, ethylsulphonyl, propylsulphonyl,isopropylsulphonyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl,ethoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.-butoxycarbonyl,benzoyl, acetyl, pyridyl, pyrimidyl, thienyl, furyl, phenyl, phenoxy,phenylthio, phenylsulphonyl, benzyloxy, benzylthio or benzylsulphonyl,

R³ - denotes hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or

- denotes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl,pentyl, isopentyl, hexyl or isohexyl, each of which can be substitutedby fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, tert.butoxy, methylthio, ethylthio,propylthio, isopropylthio, butylthio, isobutylthio, tert.butylthio,methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl,butylsulphonyl, isobutylsulphonyl, tert.butylsulphonyl, trifluoromethyl,trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert.butoxycarbonyl, benzoyl, acetyl or ethylcarbonyl, or by a group--NR⁴ R⁵, where

R⁴ and R⁵ are identical or different and denote methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert.butyl, phenyl, benzyl, acetyl,methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl orphenylsulphonyl, or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,quinolyl, isoquinolyl, thienyl, furyl, phenyl, phenoxy, phenylthio,phenylsulphonyl, benzyloxy, benzylthio or benzylsulphonyl, where theheteroaryl and aryl radicals mentioned can be substituted by fluorine,chlorine, methyl, ethyl, propyl, isopropyl, isobutyl, tert.butyl,methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert.butoxy,trifluoromethyl or trifluoromethoxy, or

- denotes thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,oxazolyl, isooxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,quinolyl, isoquinolyl, benzoxazolyl, benzimidazolyl or benzothiazolyl,where the radicals mentioned can be substituted by fluorine, chlorine,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert.butoxy, phenyl,phenoxy, trifluoromethyl, trifluoromethoxy, methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl, propoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl or tert.butoxycarbonyl, or

- denotes phenyl which can be monosubstituted, disubstituted ortrisubstituted by identical or different methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert.butyl, pentyl, isopentyl, hexyl,isohexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,tert.butoxy, methylthio, ethylthio, propylthio, isopropylthio,butylthio, isobutylthio, tert.butylthio, methylsulphonyl,ethylsulphonyl, propylsulphonyl, isopropylsulphonyl, butylsulphonyl,isobutylsulphonyl, tert.butylsulphonyl, phenyl, phenoxy, phenylthio,phenylsulphonyl, benzyl, benzyloxy, benzylthio, benzylsulphonyl,fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl ortert.butoxycarbonyl, or by a group --NR⁴ R⁵, where

R⁴ and R⁵ have the abovementioned meaning,

X - denotes a group of the formula --CH═CH-- and

A - denotes a group of the formula ##STR10## wherein R⁶ - denoteshydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl ortert.butyl and

R⁷ - denotes hydrogen, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert.butyl or benzyl, or

- denotes a sodium, potassium, calcium or magnesium or ammonium ion.

Very particularly preferred compounds are those of the general formulae(Ia) and (Ib) in which

R¹ - denotes phenyl which can be monosubstituted or disubstituted byidentical or different methyl, ethyl, propyl, isopropyl, phenoxy and/orfluorine,

R² - stands for cyclopropyl or cyclohexyl or denotes methyl, ethyl,propyl, isopropyl, butyl, isobutyl or tert.butyl, each of which can besubstituted by fluorine, chlorine, methoxy, phenyl or phenoxy,

R³ - denotes hydrogen, cyclopropyl, cyclopentyl or cyclohexyl or phenyl,or

- denotes methyl, ethyl, propyl, isopropyl, butyl or benzyl,

X - denotes a group of the formula ##STR11## and A - denotes a group ofthe formula ##STR12## wherein R⁶ - denotes hydrogen and and

R⁷ - denotes hydrogen, methyl or ethyl, or

- denotes a sodium or potassium cation.

The disubstituted pyridines of the general formula (I) according to theinvention have several asymmetric carbon atoms and can therefore existin various stereochemical forms. The invention relates both to theindividual isomers and to their mixtures.

Depending on the meaning of the groups X or the radicals A, differentstereoisomers result, which are more closely illustrated in thefollowing:

(a) If the group --X-- stands for a group of the formula --CH═CH--, thenthe compounds according to the invention can exist in two stereoisomericforms which can have the E configuration (II) or the Z configuration(III) on the double bond: ##STR13## wherein R¹, R², R³, X and A have theabovementioned meaning.

Preferred compounds of the general formula (I) are those having the Econfiguration (II).

(b) If the radical --A stands for a group of the formula ##STR14## thenthe compounds of the general formula (I) possess at least two asymmetriccarbon atoms, namely the two carbon atoms to which the hydroxyl groupsare bonded. Depending on the relative position of these hydroxyl groupsto one another, the compounds according to the invention can exist inthe erythro configuration (IV) or in the threo configuration (V).##STR15##

Again, two enantiomers each exist of the compounds in the erythro and inthe threo configuration, namely the 3R,5S-isomer or the 3S,5R-isomer(erythro form) and also the 3R,5R-isomer and the 3S,5S-isomer (threoform).

In this connection, the erythro configuration isomers are preferred, the3R,5S-isomers and also the 3R,5S-3S,5R-racemate being particularlypreferred.

(c) If the radical --A stands for a group of the formula ##STR16## thenthe disubstituted pyridines possess at least two asymmetric carbonatoms, namely the carbon atom to which the hydroxyl group is bonded, andthe carbon atom to which the radical of the formula ##STR17## is bonded.Depending on the position of the hydroxyl group to the free valency onthe lactone ring, the disubstituted pyridines can exist as thecis-lactones (VI) or as the trans-lactones (VII). ##STR18##

Again, two isomers each exist of the cis-lactone and the trans-lactone,namely the 4R,6R-isomers or the S,6S-isomers (cis-lactone), and the4R,6S-isomers or S,6R-isomers (trans-lactone). Preferred isomers are thetrans-lactones. The 4R,6S-isomers (trans) and the 4R,6S-4S,6R-racemateare particularly preferred in this case.

The following isomeric forms of the substituted pyridines may bementioned as examples: ##STR19##

Moreover, further possibilities for isomer formation result, since thedisubstituted pyridines according to the invention are substituted bytwo groups of the formula --X--A in the molecule. The invention likewiserelates to all stereoisomers which result through the second group ofthe formula --X--A, in particular in connection with the first group--X--A.

In addition, a process for the preparation of the disubstitutedpyridines of the general formula (I) ##STR20## in which R¹, R², R³, Xand A have the abovementioned meaning, has been found, characterized inthat ketones of the general formula (VIII) ##STR21## in which R¹, R² andR³ have the abovementioned meaning, and

R⁸ - stands for alkyl, are reduced, in the case of the preparation ofthe acids, the esters are hydrolyzed, in the case of the preparation ofthe lactones, the carboxylic acids are cyclized, in the case of thepreparation of the salts, either the esters or the lactones arehydrolyzed, in the case of the preparation of the ethylene compounds(X=--CH₂ --CH₂ --), the ethene compounds (X=--CH═CH--) are hydrogenatedaccording to customary methods, and, if appropriate, isomers areseparated.

The process according to the invention can be illustrated by thefollowing formula scheme: ##STR22##

Reduction can be carried out using the customary reductants, preferablyusing those which are suitable for the reduction of ketones to hydroxylcompounds. In this connection, reduction using metal hydrides or complexmetal hydrides in inert solvents, if appropriate in the presence of atrialkylborane, is particularly suitable. Reduction using complex metalhydrides such as, for example, lithium borohydride, sodium borohydride,potassium borohydride, zinc borohydride, lithium trialkyl borohydrides,sodium trialkyl borohydrides, sodium cyanoborohydride or lithiumaluminum hydride is preferred. Reduction using sodium borohydride,carried out in the presence of triethylborane, is very particularlypreferred.

Suitable solvents in this connection are the customary organic solventswhich do not change under the reaction conditions. These preferablyinclude ethers such as, for example, diethyl ether, dioxane,tetrahydrofuran or dimethoxyethane, or halogenated hydrocarbons such as,for example, dichloromethane, trichloromethane, tetrachloromethane,1,2-dichloroethane, or hydrocarbons such as, for example, benzene,toluene or xylene. It is likewise possible to employ mixtures of thesolvents mentioned.

Reduction of the ketone group to the hydroxyl group is particularlypreferably carried out under conditions in which the other functionalgroups such as, for example, the alkoxycarbonyl group, are not changed.For this, the use of sodium borohydride as a reductant in the presenceof triethylborane in inert solvents, such as preferably ether, isparticularly suitable.

Reduction in general takes place in a temperature range from -80° C. to+30° C., preferably from -78° C. to 0° C.

Reduction according to the invention is in general carried out atatmospheric pressure. However, it is also possible to carry out theprocess at underpressure or overpressure (for example in a range from0.5 to 5 bar).

In general, the reductant is employed in an amount from 1 to 2 moles,preferably from 1 to 1.5 moles, relative to 1 mole of the keto compound.

Under the abovementioned reaction conditions, the carbonyl group is ingeneral reduced to the hydroxyl group, without reduction of the doublebond to a single bond taking place.

For the preparation of compounds of the general formula (I), in which Xstands for an ethylene grouping, the reduction of the ketones (VIII) canbe carried out under those conditions under which both the carbonylgroup and the double bond are reduced.

Moreover, it is also possible to carry out the reduction of the carbonylgroup and the reduction of the double bond in two separate steps.

The carboxylic acids in the context of the general formula (I)correspond to the formula (Ic) ##STR23## in which R¹, R², R³, R⁶ and Xhave the abovementioned meaning.

The carboxylic acid esters in the context of the general formula (I)correspond to the formula (Id) ##STR24## in which R¹, R², R³, R⁶ and Xhave the abovementioned meaning, and

R⁸ - stands for alkyl.

The salts of the compounds according to the invention in the context ofthe general formula (I) correspond to the formula (Ie) ##STR25## inwhich R¹, R², R³, R⁶ and X have the abovementioned meaning, and

M^(n)⊕ stands for a cation.

The lactones in the context of the general formula (I) correspond to theformula (If) ##STR26## in which R¹, R², R³, R⁶ and X have theabovementioned meaning.

For the preparation of the carboxylic acids of the general formula (Ic)according to the invention, the carboxylic acid esters of the generalformula (Id) or the lactones of the general formula (If) are in generalhydrolyzed by customary methods. Hydrolysis in general takes place bytreating the esters or the lactones using customary bases in inertsolvents, by means of which the salts of the general formula (Ie) ingeneral first result which can then be converted in a second step intothe free acids of the general formula (Ic) by treating with acid.

Suitable bases for the hydrolysis are the customary inorganic bases.These preferably include alkali metal hydroxides or alkaline earth metalhydroxides such as, for example, sodium hydroxide, potassium hydroxideor barium hydroxide, or alkali metal carbonates such as sodium carbonateor potassium carbonate or sodium hydrogen carbonate, or alkali metalalkoxides such as sodium ethoxide, sodium methoxide, potassiummethoxide, potassium ethoxide or potassium tert.butoxide. Sodiumhydroxide or potassium hydroxide are particularly preferably employed.

Suitable solvents for the hydrolysis are water or the organic solventscustomary for hydrolysis. These preferably include alcohols such asmethanol, ethanol, propanol, isopropanol or butanol, or ethers such astetrahydrofuran or dioxane, or dimethylformamide or dimethylsulphoxide.Alcohols such as methanol, ethanol, propanol or isopropanol areparticularly preferably used. It is likewise possible to employ mixturesof the solvents mentioned.

The hydrolysis is in general carried out in a temperature range from 0°C. to +100° C., preferably from 20° C. to +80° C.

In general, the hydrolysis is carried out at atmospheric pressure.However, it is also possible to work at underpressure or overpressure(for example from 0.5 to 5 bar).

When carrying out the hydrolysis, the base is in general employed in anamount from 1 to 3 moles, preferably from 1 to 1.5 moles, relative to 1mole of the ester or the lactone. Molar amounts of reactants areparticularly preferably used.

When carrying out the reaction, the salts of the compounds according tothe invention (Ie) are formed in the first step as intermediates whichcan be isolated. The acids (Ic) according to the invention are obtainedby treating the salts (Ie) with customary inorganic acids. Thesepreferably include mineral acids such as, for example, hydrochloricacid, hydrobromic acid, sulphuric acid or phosphoric acid. It has provedadvantageous in this connection in the preparation of the carboxylicacids (Ic) to acidify the basic reaction mixture from the hydrolysis ina second step without isolation of the salts. The acids can then beisolated in a customary manner.

For the preparation of the lactones of the formula (If) according to theinvention, the carboxylic acids (Ic) according to the invention arecyclized by customary methods, for example by heating the correspondingacid in inert organic solvents, if appropriate in the presence ofmolecular sieve.

Suitable solvents in this connection are hydrocarbons such as benzene,toluene, xylene, mineral oil fractions, or tetralin or diglyme ortriglyme. Benzene, toluene or xylene are preferably employed. It islikewise possible to employ mixtures of the solvents mentioned.Particularly preferably, hydrocarbons, in particular toluene, are usedin the presence of molecular sieve.

The cyclization is in general carried out in a temperature range from-40° C. to +200° C., preferably from -25° C. to +50° C.

The cyclization is in general carried out at atmospheric pressure, butit is also possible to carry out the process at underpressure or atoverpressure (for example in a range from 0.5 to 5 bar).

Moreover, the cyclization is also carried out in inert organic solventswith the aid of cyclizing or water-eliminating agents. In thisconnection, carbodiimides are preferably used as water-eliminatingagents. Preferably, N,N'-dicyclohexylcarbodiimide paratoluenesulphonate,N-cyclohexyl-N'-[2-(N"-methylmorpholinium)-ethyl]carbodiimide orN-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride areemployed as carbodiimides.

Suitable solvents in this connection are the customary organic solvents.These preferably include ethers such as diethyl ether, tetrahydrofuranor dioxane, or chlorinated hydrocarbons such as methylene chloride,chloroform or carbon tetrachloride, or hydrocarbons such as benzene,toluene, xylene or mineral oil fractions. Chlorinated hydrocarbons suchas, for example, methylene chloride, chloroform or carbon tetrachloride,or hydrocarbons such as benzene, toluene, xylene or mineral oilfractions are particularly preferred. Chlorinated hydrocarbons such as,for example, methylene chloride, chloroform or carbon tetrachloride areparticularly preferably employed.

The reaction is in general carried out in a temperature range from 0° C.to +80° C., preferably from 10° C. to +50° C.

When carrying out the cyclization, it has proved advantageous to employthe cyclization method with the aid of carbodiimides as dehydratingagents.

The resolution of the isomers into the homogeneous stereoisomericconstituents in general takes place by customary methods, such as aredescribed, for example, by E. L. Eliel, Stereochemistry of CarbonCompounds, McGraw Hill, 1962. In this connection, the resolution of theisomers from the racemic lactone step is preferred. Particularlypreferably in this connection, the racemic mixture of the trans-lactones(VII) is converted into the diastereomeric dihydroxyamides (Ig)##STR27## by treating with either D-(+)- or L-(-)-α-methylbenzylamine bycustomary methods, which can then be resolved into the individualdiastereomers by chromatography or crystallization as is customary.Subsequent hydrolysis of the pure diastereomeric amides by customarymethods, for example by treating the diastereomeric amides withinorganic bases such as sodium hydroxide or potassium hydroxide in waterand/or organic solvents such as alcohols, for example methanol, ethanol,propanol or isopropanol, yields the corresponding pure enantiomericdihydroxy acids (Ic) which can be converted into the pure enantiomereiclactones by cyclization as described above. In general, it applies that,for the preparation of the compounds of the general formula (I)according to the invention in pure enantiomeric form, the configurationof the final product according to the method described above isdependent on the configuration of the starting materials.

The resolution of isomers is illustrated, for example, in the followingscheme: ##STR28##

The ketones (VIII) employed as starting materials are new.

A process for the preparation of the ketones of the general formula(VIII) according to the invention ##STR29## in which R¹, R² and R³ havethe abovementioned meaning and

R⁸ - stands for alkyl,

has been found, characterized in that aldehydes of the general formula(IX) ##STR30## in which R¹, R² and R³ have the abovementioned meaning,

are reacted in inert solvents with acetoacetates of the general formula(X) ##STR31## in which R⁸ has the abovementioned meaning, in thepresence of bases.

The process according to the invention can, for example, be illustratedby the following scheme: ##STR32##

Suitable bases in this connection are the customary strongly basiccompounds. These preferably include organolithium compounds such as, forexample, N-butyl-lithium, sec.butyllithium, tert.butyllithium orphenyl-lithium, or amides such as, for example, lithiumdiiso-propylamide, sodium amide or potassium amide, or lithiumhexamethyldisilylamide, or alkali metal hydrides such as sodium hydrideor potassium hydride. It is likewise possible to employ mixtures of thebases mentioned. N-Butyllithium or sodium hydride or a mixture thereofis particularly preferably employed.

Suitable solvents in this connection are the customary organic solventswhich do not change under the reaction conditions. These preferablyinclude ethers such as diethyl ether, tetrahydrofuran, dioxane ordimethoxyethane, or hydrocarbons such as benzene, toluene, xylene,cyclohexane, hexane or mineral oil fractions. It is likewise possible toemploy mixtures of the solvents mentioned. Ethers such as diethyl etheror tetrahydrofuran are particularly preferably used.

The reaction is in general carried out in a temperature range from -80°C. to +50° C., preferably from -20° C. to +30° C.

The process is in general carried out at atmospheric pressure, but it isalso possible to carry out the process at underpressure or atoverpressure, for example in a range from 0.5 to 5 bar.

When carrying out the process, the acetoacetate is in general employedin an amount from 1 to 2, preferably from 1 to 1.5 moles, relative to 1mole of the aldehyde function.

The acetoacetates of the formula (X) employed as starting materials areknown Dr can be prepared by known methods [Beilstein's Handbuch derorganischen Chemie (Beilstein's Handbook of Organic Chemistry) III, 632;438].

Examples of acetoacetates which may be mentioned for the processaccording to the invention are methyl acetoacetate, ethyl acetoacetate,propyl acetoacetate and isopropyl acetoacetate.

The aldehydes of the general formula (IX) employed as starting materialsare new.

The preparation of the aldehydes can be illustrated by the followingreaction scheme by way of example for the compounds of the type (Ia):##STR33##

In this connection, the dihydropyridines of the general formula (X) areoxidized in suitable solvents using suitable oxidants in the first step[A]. Preferably, the dihydropyridines are oxidized using2,2-dichloro-5,6-dicyano-p-benzoquinone at room temperature, or usingchromium trioxide in glacial acetic acid at elevated temperatures,preferably under reflux temperature, in chlorinated hydrocarbons suchas, for example, methylene chloride to give the pyridines of the formula(XI). In the second step [B], the pyridines (XI) are reduced to thehydroxyl compounds of the general formula (XII) using metal hydridessuch as Iithium aluminum hydride, sodium cyanoborohydride, diisobutylaluminum hydride or sodium bis-(2-methoxyethoxy)-dihydroaluminate, in atemperature range from -80° C. to +40° C., preferably from -70° C. toroom temperature, in inert solvents such as ethers, for example diethylether, dioxane or tetrahydrofuran, preferably in tetrahydrofuran. In thethird step [C], the hydroxyl compounds (XII) are oxidized to thealdehydes (XIII) by customary methods using oxidants such as pyridiniumchlorochromate, if appropriate in the presence of aluminum oxide, ininert solvents such as chlorinated hydrocarbons, preferably methylenechloride, at room temperature or using trifluoroacetic acid and dimethylsulphoxide (Swern oxidation) or, however, according to other methodscustomary for the oxidation of hydroxymethyl compounds to aldehydes. Inthe fourth step [D], the aldehydes (XIII) are converted into thecompounds (IX) by reacting with diethyl-2-(cyclohexylamino)-vinylphosphonate in inert solvents such as ethers, preferably intetrahydrofuran in the presence of sodium hydride, in a temperaturerange from -20° C. to +30° C., preferably from -5° C. to roomtemperature.

The dihydropyridines of the general formula (X) employed as startingmaterials are known or can be prepared by known methods [EP-A No.88,276; DE-A No. 2,847,236].

The compounds of the general formula (I) according to the invention areactive compounds for medicaments. In particular, they are inhibitors of3-hydroxy-3-methyl-glutaryl coenzyme A (HGM-CoA) reductase andconsequently inhibitors of cholesterol biosynthesis. They can thereforebe employed for the treatment of hyperlipoproteinaemia, lipoproteinaemiaor arteriosclerosis. The active compounds according to the invention inaddition cause a lowering of the cholesterol content in the blood.

The new active compounds can be converted in a known manner into thecustomary formulations, such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, non-toxic, pharmaceutically suitable excipients or solvents. Inthis connection, the therapeutically active compound should in each casebe present in a concentration of about 0.5 to 98% by weight, preferably1 to 90% by weight, of the total mixture, i.e. in amounts which aresufficient to achieve the indicated dosage range.

The formulations are prepared, for example, by extending the activecompounds with solvents and/or excipients, if appropriate usingemulsifiers and/or dispersing agents, where, for example, in the case ofthe use of water as a diluent, organic solvents may optionally be usedas auxiliary solvents.

Auxiliaries which may be mentioned, for example, are: water, non-toxicorganic solvents, such as paraffins (for example mineral oil fractions),vegetable oils (for example groundnut/sesame oil), alcohols (forexample: ethyl alcohol, glycerol), excipients, such as, for example,ground natural minerals (for example kaolins, clays, talc, chalk),ground synthetic minerals (for example highly disperse silica,silicates), sugars (for example sucrose, lactose and dextrose),emulsifiers (for example polyoxyethylene fatty acid esters,polyoxyethylene fatty alcohol ethers, alkyl sulphonates and arylsulphonates), dispersing agents (for example lignin sulphite wasteliquors, methylcellulose, starch and polyvinylpyrrolidone) andlubricants (for example magnesium stearate, talc, stearic acid andsodium lauryl sulphate).

Administration takes place in a customary manner, preferably orally,parenterally, perlingually or intravenously. In the case of oraladministration, tablets can, of course, also contain additives, such assodium citrate, calcium carbonate and dicalcium phosphate together withvarious additive substances, such as starch, preferably potato starch,gelatin and the like, in addition to the excipients mentioned.Furthermore, lubricants, such as magnesium stearate, sodium laurylsulphate and talc can also be used for tableting. In the case of aqueoussuspensions, various flavor-improvers or colourants can be added to theactive compound in addition to the abovementioned auxiliaries.

In the case of parenteral administration, solutions of the activecompounds can be employed using suitable liquid excipients.

In general, it has proved advantageous with intravenous administrationto administer amounts of about 0.001 to 1 mg/kg, preferably about 0.01to 0.5 mg/kg of body weight to obtain effective results, and with oraladministration the dosage is about 0.01 to 20 mg/kg, preferably 0.1 to10 mg/kg of body weight.

Nevertheless, it may be necessary to depart from the amounts mentioned,depending on the body weight or the type of administration route,individual behavior towards the medicament, the manner of itsformulation and the point in time or interval at which administrationtakes place. Thus, in some cases it is sufficient to manage with lessthan the previously mentioned minimum amount, whereas in other cases theupper limit mentioned must be exceeded. In the case of theadministration of larger amounts, it may be advisable to divide theseinto several individual doses over the day.

PREPARATION EXAMPLES Example 1(E/Z)-4-Carboxyethyl-5-(4-fluorophenyl)-2-methyl-pent-4-en-3-one##STR34##

62 g (0.5 mol) of 4-fluorobenzaldehyde and 79 g (0.5 mol) of ethylisobutanoylacetate are initially introduced into 300 ml of dryisopropanol and a mixture of 2.81 ml (28 mmol) of piperidine and 1.66 ml(29 mmol) of acetic acid in 40 ml of isopropanol is added. The mixtureis stirred for 48 h at room temperature and concentrated in vacuo, andthe residue is distilled in a high vacuum.

B.p. 0.5 mm : 127° C.

Yield: 108.7 g (82.3% of theory)

Example 2 Diethyl1,4-dihydro-2,6-diisopropyl-4-(4-fluorophenyl)pyridine-3,5-dicarboxylate##STR35##

98 g (0.371 mol) of the compound from Example 1 are boiled under refluxfor 18 hours with 58.3 g (0.371 mol) of ethyl3-amino-4-methyl-pent-2-enoate in 300 ml of ethanol. The mixture iscooled to room temperature, the solvent is evaporated off in vacuo andthe unreacted starting materials are removed by distillation at 130° C.in a high vacuum. The remaining syrup is stirred with n-hexane and thedeposited precipitate is filtered off with suction, washed with n-hexaneand dried in a desiccator.

Yield: 35 g (23.4% of theory)

¹ H-NMR (CDCl₃): δ=1.1-1.3 (m, 18H); 4.05-4.25 (m, 6H); 5.0 (s, 1H);6.13 (s, 1H); 6.88 (m, 2H); 7.2 (m, 2H).

Example 3 Diethyl2,6-diisopropyl-4-(4-fluorophenyl)-pyridine-3,5-dicarboxylate ##STR36##

3.8 g (16.4 mmol) of 2,3-dichloro-5,6-dicyano-p-benzoquinone are addedto a solution of 6.6 g (16.4 mmol) of the compound from Example 2 in 200ml of methylene chloride p.a. and the mixture is stirred for 1 h at roomtemperature. It is then filtered over kieselgur with suction, themethylene chloride phase is extracted three times using 100 ml of watereach time and dried over magnesium sulphate. After concentrating invacuo, the residue is chromatographed on a column (100 g of silica gel70-230 mesh, φ 3.5 cm, using ethyl acetate/petroleum ether (1:9).

Yield 5.8 g (87.9% of theory)

¹ H-NMR (CDCl₃): δ=0.98 (t, 6H); 1.41 (d, 12H); 3.1 (m, 2H); 4.11 (q,4H); 7.04 (m, 2H); 7.25 (m, 2H).

Example 43,5-Dihydroxymethyl-2,6-diisopropyl-4-(4-fluorophenyl)-pyridine##STR37##

22.8 ml (80 mmol) of a 3.5 molar solution of sodiumbis-(2-methoxyethoxy)-dihydroaluminate in toluene are added undernitrogen to a solution of 4.6 g (11.4 mmol) of the compound from Example3 in 100 ml of dry tetrahydrofuran at -10° C. to -5° C. The mixture isstirred overnight at room temperature and then warmed to 40° C. for 5 h.After cooling again to 0° C., 100 ml of water are cautiously addeddropwise and the mixture is extracted three times using 100 ml of ethylacetate each time. The combined organic phases are washed with saturatedsodium chloride solution, dried over magnesium sulphate and concentratedin vacuo. The residue is chromatographed on a column (100 g of silicagel 70-230 mesh, φ 3.5 cm, using ethyl acetate/petroleum ether (6:4)).

Yield: 2.4 g (66.7% of theory)

¹ H-NMR (CDCl₃): δ=1.35 (d, 12H); 3.43 (m, 2H); 4.47 (d, 4H); 7.05-7.3(m, 4H).

Example 5 2,6-Diisopropyl-4-(4-fluorophenyl)-pyridine-3,5-dicarbaldehyde##STR38##

10.3 g (48 mmol) of pyridinium chlorochromate and 4.9 g (48 mmol) ofneutral alumina are added to a solution of 3.8 g (12 mmol) of thecompound from Example 4 in 100 ml of methylene chloride p.a. and themixture is stirred for 1 h at room temperature. The mixture is filteredover kieselgur with suction and washed with 300 ml of methylenechloride. The methylene chloride phase is concentrated in vacuo and theresidue is chromatographed on a column (150 g of silica gel 70-230 mesh,φ3.5 cm, using ethyl acetate/petroleum ether 2:8).

Yield: 3.2 g (85.3% of theory)

¹ H-NMR (CDCl₃): δ=1.33 (d, 12H); 3.85 (m, 2H); 7.1-7.32 (m, 4H); 9.8(s, 2H).

Example 6(E,E)-2,6-Diisopropyl-4-(4-fluorophenyl)-3,5-di(prop-2-en-1-al-3-yl)-pyridine##STR39##

3.1 g (12 mmol) of diethyl 2-(cyclohexylamino)vinyl phosphonatedissolved in 20 ml of dry tetrahydrofuran are added dropwise undernitrogen to a suspension of 0.36 g (12 mmol) of 80% pure sodium hydridein 20 ml of dry tetrahydrofuran at -5° C. After 30 minutes, 1.6 g (5mmol) of the compound from Example 5 in 20 ml of dry tetrahydrofuran areadded dropwise at the same temperature and the mixture is warmed toreflux for 30 minutes. After cooling to room temperature, the batch isadded to 200 ml of ice-cold water and extracted three times using 100 mlof ethyl acetate each time. The combined organic phases are washed withsaturated sodium chloride solution and dried over magnesium sulphate.After concentrating in vacuo, the residue is taken up in 50 ml oftoluene, a solution of 2 g (15 mmol) of oxalic acid dihydrate in 25 mlof water is added and the mixture is warmed to reflux for 30 minutes.After cooling to room temperature, the phases are separated, and theorganic phase is washed with saturated sodium chloride solution, driedover magnesium sulphate and concentrated in vacuo. The residue ischromatographed on a column (100 g of silica gel 70-230 mesh, φ3.5 cm,using ethyl acetate/petroleum ether 2:8).

Yield: 920 mg (50% of theory)

¹ H-NMR (CDCl₃): δ=1.33 (d, 12H); 3.33 (m, 2H); 6.03 (dd, 2H); 7.0-7.35(m, 6H); 9.42 (d, 2H).

Example 7 2,6-Diisopropyl-4-(4-fluorophenyl)-3,5-di-(methyl(E)-5-hydroxy-3-oxo-hept-6-enoat-7-yl)-pyridine ##STR40##

1.16 g (10 mmol) of methyl acetate in 5 ml of dry tetrahydrofuran areadded dropwise under nitrogen to a suspension of 360 mg (12 mmol) of 80%pure sodium hydride in 30 ml of dry tetrahydrofuran at -5° C. After 15minutes, 6.2 ml (10 mmol) of 15% strength butyllithium in n-hexane areadded dropwise at the same temperature and the mixture is stirred for 15minutes, 912 mg (2.5 mmol) of the compound from Example 6 dissolved in20 ml of dry tetrahydrofuran are subsequently added dropwise and themixture is stirred at -5° C. for 30 minutes. 3 ml of 50% strength aceticacid are cautiously added to the reaction solution, and the mixture isdiluted using 100 ml of water and extracted three times using 100 ml ofether each time. The combined organic phases are washed twice withsaturated sodium hydrogen carbonate solution and once with saturatedsodium chloride solution, dried over magnesium sulphate and concentratedin vacuo. The residue is chromatographed on a column (80 g of silica gel70-230 mesh, 3 cm, using ethyl acetate/petroleum ether 1:1 ).

Yield: 800 mg (53.6% of theory)

¹ H-NMR (CDCl₃): δ=1.25 (m, 12H); 2.47 (m, 4H); 3.25 (m, 2H); 3.42 (s,4H); 3.73 (s, 6H); 4.5 (m, 2H); 5.25 (dd, 2H); 6.35 (dd, 2H); 7.0 (m,4H).

Example 8 2,6-Diisopropyl-4-(4-fluorophenyl)-3,5-di-(methylerythro-(E)-3,5-dihydroxy-hept-6-enoat-7-yl)-pyridine ##STR41##

3.2 ml (3.2 mmol) of 1M triethylborane solution in tetrahydrofuran areadded at room temperature to a solution of 776 mg (1.3 mmol) of thecompound from Example 7 in 30 ml of dry tetrahydrofuran, air is passedthrough the solution for 5 minutes and it is cooled to -30° C. internaltemperature. 122 mg (3.2 mmol) of sodium borohydride are added and,slowly, 2.5 ml of methanol, the mixture is stirred for 30 minutes at-30° C. and then a mixture of 10 ml of 30% strength hydrogen peroxideand 20 ml of water is added. The temperature is allowed to climb to 0°C. in the course of this and the mixture is stirred for a further 30minutes. The mixture is extracted three times using 50 ml of ethylacetate each time, and the combined organic phases are washed once eachwith saturated sodium hydrogen carbonate solution and saturated sodiumchloride solution, dried over magnesium sulphate and concentrated invacuo. The residue is chromatographed on a column (50 g of silica gel230-400 mesh, φ2.5 cm, using ethyl acetate/petroleum ether 1:1).

Yield: 400 mg (51.4% of theory) hu H-NMR (CDCl₃): δ=12.5 (m, 12H); 1.4(m, 4H); 2.42 (m, 4H); 3.3 (m, 2H); 3.72 (s, 6H); 4.1 (m, 2H); 4.3 (m,2H); 5.25 (dd, 2H); 6.3 (dd, 2H); 7.0 (m, 4H).

Example 9 (E/Z)-4-Carboxyethyl-2-methyl-5-phenyl-pent-4-en-3-one##STR42##

6.9 g (0.44 mol) of ethyl isobutanoylacetate and 6.3 g (0.44 mol) ofbenzaldehyde are initially introduced into 300 ml of isopropanol, amixture of 2.5 ml (25 mmol) of piperidine and 1.5 ml (26 mmol) of aceticacid in 40 ml of isopropanol is added and the mixture is stirred for 24h at room temperature. The mixture is concentrated in vacuo and theresidue is distilled in a high vacuum.

B.p. 0.5 mm : 130° C.

Yield: 60.7 g (56.2% of theory)

Example 10 Diethyl1,4-dihydro-2,6-diisopropyl-4-phenyl-pyridine-3,5-dicarboxylate##STR43##

29.5 g (120 mmol) of the compound from Example 9 and 18.8 g (120 mmol)of ethyl 3-amino-4-methyl-pent-2-en-oate are boiled under reflux in 150ml of ethanol for 8 hours. The mixture is cooled and concentrated invacuo, and the residue is chromatographed on a column (500 g of silicagel, 70-230 mesh, φ 5 cm, using ethyl acetate/petroleum ether 1:9).

Yield: 7.2 g (15.1% of theory)

¹ H-NMR (CDCl₃): δ=1.2 (m, 18 H); 4.1 (m, 4H); 4.21 (m, 2H); 5.02 (s,1H); 6.13 (s, 1H); 7.2 (m, 5H).

Example 11 Diethyl 2,6-diisopropyl-4-phenyl-pyridine-3,5dicarboxylate##STR44##

7.2 g (18.2 mmol) of the compound from Example 10 are reactedanalogously to Example 3. Yield: 6.4 g (88.8% of theory)

Example 12 3,5-Dihydroxymethyl-2,6-diisopropyl-4-phenyl-pyridine##STR45##

40.5 ml (40.5 mmol) of a 1 molar solution of lithium aluminum hydride inether are added dropwise under nitrogen to a solution of 6.4 g (16.2mmol) of the compound from Example 11 in 100 ml of dry tetrahydrofuranat 0° C. The mixture is stirred overnight at room temperature, warmed to50° C. for 3 h and cooled again to 0° C. 200 ml of water are cautiouslyadded dropwise to the mixture, and it is filtered over kieselguhr withsuction and washed with 250 ml of ether. The organic phase is separated,washed once with saturated sodium chloride solution, dried overmagnesium sulphate and concentrated in vacuo. The residue is stirredwith petroleum ether, and the precipitate is filtered off with suctionand dried in a desiccator.

Yield: 4 g (83.3% of theory)

¹ H-NMR (CDCl₃): δ=1.3 (d, 12H); 3.5 (m, 2H); 4.3 (d, 4H); 7.35 (m, 5H).

Example 13 2,6-Diiopropyl-4-phenyl-pyridine-3,5-dicarbaldehyde ##STR46##

4 g (13.3 mmol) of the compound from Example 12 are reacted analogouslyto Example 5. Yield: 3.4 g (87.2% of theory)

¹ H-NMR (CDCl₃): δ=1.35 (d, 12H); 3.4 (m, 2H); 7.3 (m, 2H); 7.5 (m, 3H);9.3 (s, 2H).

Example 14(E,E)-2,6-Diisopropyl-4-phenyl-3,5-di-(prop-2-en-1-al-3-yl)-pyridine##STR47##

3.35 g (11.4 mmol) of the compound from Example are reacted analogouslyto Example 6. Yield: 2.7 g (67.5% of theory)

¹ H-NMR (CDCl₃): δ=1.35 (d, 12H); 3.47 (m, 2H); 6.04 (dd, 2H); 7.0-7.45(m, 7H); 9.4 (d, 2H).

Example 15 2,6-Diisopropyl-4-phenyl-3,5-di-(methyl(E)-5-hydroxy-3-oxo-hept-6-enoat-7-yl)-pyridine ##STR48##

2.7 g (7.8 mmol) of the compound from Example 14 are reacted analogouslyto Example 7. Yield: 3.2 g (71.1% of theory)

¹ H-NMR (CDCl₃): δ=1.25 (m, 12H); 2.35 (m, 4H); 3.27 (m, 2H); 3.40 (s,4H); 3.75 (s, 6H); 4.38 (m, 2H); 5.25 (dd, 2H); 6.37 (dd, 2H); 7.02 (m,2H); 7.30 (m, 3H).

Example 16 2,6-Diisopropyl-4-phenyl-3,5-di-(methylerythro-(E)-3,5-dihydroxy-hept-6-enoat-7-yl)-pyridine ##STR49## 3.2 g(5.5 mmol) of the compound from Example 15 are reacted analogously toExample 8. Yield: 2 g (62.5% of theory)

¹ H-NMR (CDCl₃): δ=1.25 (m, 12H); 1.3-1.7 (m, 4H); 2.39 (m, 4H); 3.2-3.4(m, 2H); 3.71 (s, 6H); 4.02 (m, 2H); 4.27 (m, 2H); 5.3 (m, 2H); 6.32 (m,2H); 7.0 (m, 2h); 7.25 (m, 3H).

Example 17 (E/Z)-2-Ethoxycarbonyl-1-(4-fluorophenyl)-but-2-en-3-one##STR50##

62 g (0.5 mol) of 4-fluorobenzaldehyde and 53.9 ml (0.5 mol) of methylacetoacetate are initially introduced into 30 ml of isopropanol, amixture of 2.81 ml (28 mmol) of piperidine and 1.66 ml (29 mmol) ofacetic acid in 40 ml of isopropanol is added and the mixture is stirredfor 48 h at room temperature. The mixture is concentrated in vacuo andthe residue is distilled in a high vacuum.

B.p. 0.5 mm: 138° C.

Yield: 50.5 g (45.5% of theory)

Example 18 Dimethyl1,4-dihydro-2,6-dimethyl-4-(4-fluorophenyl)-pyridine-3,5-dicarboxylate##STR51##

33.3 g (0.15 mol) of the compound from Example 17 are boiled underreflux for 4 h with 17.3 g (0.15 mol) of methyl 3-aminocrotonate in 150ml of ethanol. The mixture is cooled to 0° C., and the depositedprecipitate is filtered off with suction, washed with a little petroleumether and dried in a desiccator.

Yield: 32 g (66.8% of theory)

¹ H-NMR (CDCl₃): δ=2.33 (s, 6H); 3.65 (s, 6H); 4.99 (s, 1H); 5.77 (s,1H); 6.89 (m, 2H); 7.22 (m, 2H).

Example 19 Dimethyl2,6-dimethyl-4-(4-fluorophenyl)-pyridine-3,5-dicarboxylate ##STR52##

32 g (0.1 mol) of the compound from Example 18 are reacted analogouslyto Example 3.

Yield: 27.2 g (87% of theory)

¹ H-NMR (CDCl₃): δ=2.59 (s, 6H); 3.56 (s, 6H); 7.08 (m, 2H); 7.25 (m,2H).

Example 20 3,5-Dihydroxymethyl-2,6-dimethyl-4-(4-fluorophenyl)pyridine##STR53##

25 ml (87.5 mmol) of a 3.5 molar solution of sodiumbis-(2-methoxyethoxy)-dihydroaluminate in toluene are added undernitrogen to a solution of 7.9 g (25 mmol) of the compound from Example19 in 100 ml of dry tetrahydrofuran at 0° C. The mixture is stirred atroom temperature for 6 h, cooled again to 0° C. and 200 ml of water areslowly added dropwise. The mixture is extracted three times using 150 mlof ethyl acetate each time, the combined organic phases are washed oncewith saturated sodium chloride solution, dried over magnesium sulphateand concentrated in vacuo. The residue is stirred with ether, filteredoff with suction and dried in a desiccator.

Yield: 3.5 g (53.8% of theory)

¹ H-NMR (CDCl₃): δ=2.81 (s, 6H); 4.28 (d, 4H); 7.1 (m, 2H); 7.3 (m, 2H).

Example 21 2,6-Dimethyl-4-(4-fluorophenyl)-pyridine-3,5-carbaldehyde##STR54##

3.5 g (13.4 mmol) of the compound from Example 20 are reactedanalogously to Example 5.

Yield: 1.7 g (53% of theory)

¹ H-NMR (CDCl₃): δ=2.88 (s, 6H); 7.28 (m, 4H); 9.82 (s, 2H).

Example 22(E,E)-2,6-Dimethyl-4-(4-fluorophenyl)-3,5-bis-(prop-en-1-al-3-yl)-pyridine##STR55## 1.7 g (7 mmol) of the compound from Example 21 are reactedanalogously to Example 6.

Yield: 1 g (47.6% of theory)

¹ H-NMR (CDCl₃): δ=2.7 (s, 6H); 6.15 (dd, 2H); 7.15 (m, 6H); 9.43 (d,2H).

Example 23 2,6-Dimethyl-4-(4-fluorophenyl)-3,5-di-(methyl(E)-5-hydroxy-3-oxo-hept-6-enoat-7-yl)-pyridine ##STR56##

1 g (3.2 mmol) of the compound from Example 22 are reacted analogouslyto Example 7.

Yield: 1 g (57% of theory)

¹ H-NMR (CDCl₃): δ=2.50 (m, 4H); 2.55 (s, 6H); 3.45 (s, 4H); 3.73 (s,6H); 4.52 (m, 2H); 5.35 (dd, 2H); 6.28 (d, 2H); 7.05 (m, 4H) ppm.

Example 24 2,6-Dimethyl-4-(4-fluorophenyl)-3,5-di-(methylerythro-(E)-3,5-dihydroxy-hept-6-enoat-7-yl)-pyridine ##STR57##

1 g (1.8 mmol) of the compound from Example 23 are reacted analogouslyto Example 8.

Yield: 0.7 g (69.9% of theory)

¹ H-NMR (CDCl₃): δ=1.20-1.60 (m, 4H); 2.43 (m, 4H); 2.54 (s, 6H); 3.72(s, 6H); 4.09 (m, 2H); 4.33 (m, 2H); 5.37 (dd, 2H); 6.22 (d, 2H); 7.03(m, 4H) ppm.

Example 25 5-Ethyl 5-methyl1,4-dihydro-4-(4-fluorophenyl)-2-isopropyl-6-methylpyridine-3,5-dicarboxylate##STR58##

15 g (56.8 mol) of the compound from Example 1 and 6.5 g (56.8 mmol) ofmethyl 3-aminocrotonate are boiled to reflux in 150 ml of ethanol for 20h. The mixture is cooled, filtered and concentrated in vacuo. Theresidue is chromatographed on a column (250 g of silica gel 70-230 mesh,φ 4.5 cm, using ethyl acetate/petroleum ether 3:7).

Yield: 13.6 g (66.3% of theory)

¹ H-NMR (CDCl₃): δ=1.2 (m, 9H); 2.35 (s, 3H); 3.65 (s, 3H); 4.12 (m,3H); 4.98 (s, 1H); 5.75 (s, 1H); 6.88 (m, 2H); 7.25 (m, 2H).

Example 26 3-Ethyl 5-methyl4-(4-fluorophenyl)-2-isopropyl-6-methylpyridine-3,5-dicarboxylate##STR59##

13.5 g (37.4 mmol) of the compound from Example 25 are reactedanalogously to Example 3.

Yield: 9.5 g (79.9% of theory)

¹ H-NMR (CDCl₃): δ=0.98 (t, 3H); 1.31 (d, 6H); 2.6 (s, 3H); 3.11 (m,1H); 3.56 (s, 3H); 4.03 (q, 2H); 7.07 (m, 2H); 7.25 (m, 2H).

Example 273,5-Dihydroxymethyl-4-(4-fluorophenyl)-2-isopropyl-6-methyl-pyridine##STR60##

20.7 g (57.7 mmol) of the compound from Example 26 dissolved in 50 ml ofabsolute tetrahydrofuran are slowly added dropwise under nitrogen to asuspension of 6 g (158 mmol) of lithium aluminum hydride in 200 ml ofabsolute tetrahydrofuran at 60° C. The mixture is heated to reflux for 1h, cooled to 0° C. and 18 ml of water are cautiously added. 6 ml of 10%strength potassium hydroxide solution are added to the mixture, it isfiltered off from the precipitate with suction and the residue is boiledtwice using 250 ml of ether each time. The combined mother liquors aredried over magnesium sulphate and concentrated in vacuo. The residue isstirred with petroleum ether, filtered off with suction and dried in adesiccator.

Yield: 11.5 g (68.9% of theory)

¹ H-NMR (CDCl₃): δ=1.3 (d, 6H); 2.69 (s, 3H); 3.51 (m, 1H); 4.3 (m, 4H);7.1 (m, 2H); 7.3 (m, 2H).

Example 284-(4-Fluorophenyl)-2-isopropyl-6-methyl-pyridine-3,5-dicarbaldehydedicarbaldehyde ##STR61##

11.5 g (40 mmol) of the compound from Example 27 are reacted analogouslyto Example 5.

Yield: 7.3 g (64% of theory)

¹ H-NMR (CDCl₃): δ=1.32 (d, 6H); 2.88 (s, 3H); 3.87 (m, 1H); 7.25 (m,4H); 9.81 (d, 2H).

Example 29(E,E)-4-(4-Fluorophenyl)-2-isopropyl-6-methyl-3,5-di-(prop-2-en-1-al-3-yl)-pyridine##STR62##

7.3 g (21.7 mmol) of the compound from Example are reacted analogouslyto Example 6.

Yield: 6.35 g (86.9% of theory)

¹ H-NMR (CDCl₃): δ=1.32 (d, 6H); 2.7 (s, 3H); 3.34 (m, 1H); 6.02 (dd,1H); 6.15 (dd, 1H); 7.0-7.35 (m, 6H); 9.42 (d, 1H); 9.43 (d, 1H).

Example 30 4-(4-Fluorophenyl)-2-isopropyl-6-methyl-3,5-di-(methyl(E)-5-hydroxy-3-oxo-hept-6-enoat-7-yl)-pyridine ##STR63##

6.3 g (18.8 mol) of the compound from Example 29 are reacted analogouslyto Example 7.

Yield: 5.7 g (53.5% of theory)

¹ H-NMR (CDCl₃): δ=1.25 (d, 6H); 2.42 (m, 2H); 2.53 (m, 2H); 2.57 (s,3H); 3.28 (m, 1H); 3.42 (s, 2H); 3.43 (s, 2H); 3.75 (s, 6H); 4.52 (m,2H); 5.25 (dd, 1H); 5.36 (dd, 1H); 6.28 (d, 1H); 6.37 (d, 1H); 6.90-7.20(m, 4H).

Example 31 4-(4-Fluorophenyl)-2-isopropyl-6-methyl-3,5-di-(methylerythro-(E)-3,5-dihydroxy-hept-6-enoat-7-yl)-pyridine ##STR64##

5.7 g (10 mmol) of the compound from Example 30 are reacted analogouslyto Example 8.

Yield: 2.9 g (50.8% of theory)

¹ 1 H-NMR (CDCl₃): δ=1.25 (m, 6H); 1.2 - 1.5 (m, 4H); 2.41 (m, 4H); 2.57(s, 3H); 3.3 (m, 1H); 3.72 (s, 6H);4.1 (m, 2H); 4.3 (m, 2H); 5.15-5.5(m, 2H); 6.15-6.45 (m, 2H); 7.0 (m, 4H).

Example 32 Diethyl1,4-dihydro-2-ethyl-4-(4-fluorophenyl)-6-isopropyl-pyridine-3,5-dicarboxylate##STR65##

9.5 g (73.6 mmol) of ethyl 3-amino-pent-2-enoate and 19.4 g (73.6 mmol)of the compound from Example are boiled under reflux for 5 hours in 200ml of n-butanol. The mixture is cooled to room temperature, the solventis concentrated in vacuo and the residue is chromatographed on a column(silica gel 70-230 mesh, using petroleum ether/ethyl acetate 9:1).

Yield: 5.3 g (19.3% of theory)

Example 33 2-Ethyl-4-(4-fluorophenyl)-6-isopropyl-3,5-di-(methylerythro-(E)-3,5-dihydroxy-hept-6-enoat-7-yl)-pyridine ##STR66##

Example 33 was prepared from the compound from Example 32, in analogy tothe reactions of Examples 3, 27, 5, 6, 7 and 8:

¹ H-NMR (CDCl₃): δ=1.28 (m, 9H); 1.43 (m, 4H); 2.42 (m, 4H); 2.82 (q,2H); 3.32 (m, 1H); 3.72 (s, 6H); 4.09 (m, 2H); 4.32 (m, 2H); 5.28 (m,2H); 6.30 (m, 2H); 7.00 (m, 4H) ppm

Example 34 Diethyl1,4-dihydro-4-(4-fluorophenyl)-2-isopropyl-6-n-propyl-pyridine-3,5-dicarboxylate##STR67##

5.8 g (36.8 mmol) of ethyl 3-amino-hex-2-enoate and 9.7 g (36.8 mmol) ofthe compound from Example 1 are boiled under reflux for 48 hours in 100ml of ethanol p.A. The mixture is cooled, the solvent is concentrated invacuo and the residue is chromatographed on a column (silica gel 70-230mesh, using petroleum ether/ethyl acetate 8:2).

Yield: 2.6 g (17.7% of theory).

Example 35 4-(4-Fluorophenyl)-2-isopropyl-6-n-propyl-3,5-di-(methylerythro-(E)-3,5-dihydroxy-hept-6-enoat-7-yl)-pyridine ##STR68##

Example 35 was prepared from the compound from Example 34, in analogy tothe reactions of Examples 3, 27, 5, 6, 7 and 8.

¹ H-NMR (CDCl₃): δ=0.98(t, 3H); 1.22 (d, 6H); 1.38 (m, 4H); 1.77 (m,2H); 2.40 (m, 4H); 2.78 (m, 2H); 3.28 (m, 1H); 3.70 (s, 6H); 4.05 (m,2H); 4.28 (m, 2H); 5.25 (m, 2H); 6.28 (m, 2H); 6.95 (m, 4H) ppm.

Example 36 Diethyl1,4-dihydro-2-n-butyl-4-(4-fluorophenyl)-6-isopropyl-pyridine-3,5-dicarboxylate##STR69##

6.3 g (36.8 mmol) of ethyl 3-amino-hept-2-enoate and 9.7 g (36.8 mmol)of the compound from Example 1 are reacted analogously to Example 34.

Yield: 2.5 g (16.4% of theory)

Example 37 2-n-Butyl-4-(4-fluorophenyl)-6-isopropyl-3,5-di-(methylerythro-(E)-3,5-dihydroxy-hept-6-enoat-7-yl)-pyridine ##STR70##

Example 37 was prepared from the compound from Example 36, in analogy tothe reactions of Examples 3, 27, 5, 6, 7 and 8.

Example 38 Diethyl1,4-dihydro-2-benzyl-4-(4-fluorophenyl)-6-isopropyl-pyridine-3,5-dicarboxylate##STR71##

7.4 g (36.8 mmol) of ethyl 3-amino-4-phenylcrotonate and 9.7 g (36.8mmol) of the compound from Example 1 are reacted analogously to Example34.

Yield: 2.1 g (12.6% of theory).

Example 392-Benzyl-4-(4-fluorophenyl)-6-isopropyl-3,5-di-(methylerythro-(E)-3,5-dihydroxy-hept-6-enoat-7-yl)-pyridine##STR72##

Example 39 was prepared from the compound from Example 38, in analogy tothe reactions of Examples 3, 27, 5, 6, 7 and 8.

¹ H-NMR (CDCl₃): δ=1.10-1.50 (m, 10H); 2.40 (m, 4H); 3.32 (m, 1H); 3.72(s, 3H); 3.73 (s, 3H); 3.98 (m, 1H); 4.08 (m, 1H); 4.18 (m, 1H); 4.21(s, 2H); 4.28 (m, 1H); 5.13 (dd, 1H); 5.27 (dd, 1H); 6.25 (d, 1H); 6.33(d, 1H); 6.97 (m, 4H); 7.25 (m, 5H) ppm.

Example 40(E/Z)-2-Carboxyethyl-1-cyclopropyl-3-(4-fluorophenyl)-prop-2-en-1-one##STR73##

39 g (0.25 mol) of ethyl cyclopropylcarbonylacetate and 31 g (0.25 mol)of 4-fluorobenzaldehyde are initially introduced into 150 ml of dryisopropanol and a mixture of 1.4 ml (14 mmol) of piperidine and 0.83 ml(14.5 mmol) of acetic acid in 20 ml of isopropanol is added. The mixtureis stirred for 48 hours at room temperature and concentrated in vacuo,and the residue is distilled in a high vacuum.

B.p. 0.5 mm: 140° C.

Yield: 52.3 g (79.8% of theory)

Example 41 Diethyl1,4-dihydro-2-cyclopropyl-4-(4-fluorophenyl)-6-isopropyl-pyridine-b3,5-dicarboxylate ##STR74##

39.3 g (0.15 mol) of the compound from Example 40 and 23.6 g (0.15 mol)of ethyl 3-amino-4-methyl-pent-2-enoate are boiled under refluxovernight in 150 ml of ethylene glycol. After cooling to roomtemperature, the mixture is extracted several times using ether, thecombined ether phases are washed three times with 10% strengthhydrochloric acid, and once each with water and saturated sodiumhydrogen carbonate solution, dried over magnesium sulphate andconcentrated in vacuo. The residue is stirred with petroleumether/ether, filtered off with suction and dried in a desiccator.

Yield: 22.8 g (37.9% of theory)

¹ H-NMR (CDCl₃): δ=0.65 (m, 2H); 1.03 (m, 2H); 1.15 (m, 13H); 2.78 (m,1H); 4.15 (m, 4H); 5.03 (s, 1H); 5.72 (s, 1H); 6.90 (m, 2H); 7.22 (m,2H) ppm.

Example 42 2-Cyclopropyl-4-(4-fluorophenyl)-6-isopropyl-3,5-di-(methylerythro-(E)-3,5-dihydroxy-hept-6-enoat-7-yl)-pyridine ##STR75##

Example 42 was prepared from the compound from Example 41, in analogy tothe reactions of Examples 3, 27, 5, 6, 7 and 8.

¹ H-NMR (CDCl₃): δ=0.90 (m, 2H); 1.20 (d, 6H); 1.10-1.60 (m, 6H); 2.25(m, 1H); 2.43 (m, 4H); 3.25 (m, 1H); 3.73 (s, 6H); 4.08 (m, 2H); 4.30(m, 2H); 5.22 (dd, 1H); 5.53 (dd, 1H); 6.30 (m, 2H); 6.98 (m, 4H) ppm.

Example 43 Ethyl 3-amino-3-cyclopropyl-acrylate ##STR76##

1.1 g of p-toluenesulphonic acid are added to 49.9 g (0.32 mol) of ethylcyclopropylcarbonylacetate in 200 ml of dry toluene and the mixture issaturated with ammonia gas at room temperature with stirring. Afterallowing to stand overnight, the mixture is boiled under reflux for 8hours in a water separator, ammonia gas being continuously introduced.The mixture is allowed to cool overnight and is filtered, and thetoluene solution is concentrated in vacuo and removed by distillation ina high vacuum up to 65° C. from unreacted starting material. Thesubstance is subsequently found in the residue. Yield: 11.9 g (24% oftheory).

Example 44 Diethyl1,4-dihydro-2,6-dicyclopropyl-4-(4-fluorophenyl)-pyridine-3,5-dicarboxylate##STR77##

6.2 g (40 mmol) of the compound from Example 43 and 10.5 g (40 mmol) ofthe compound from Example 40 are dissolved in 100 ml of ethylene glycoland the mixture is boiled to reflux overnight. After cooling to roomtemperature, the mixture is extracted several times using ether, and theorganic phase is washed once each with 10% strength hydrochloric acid,saturated sodium bicarbonate solution and water, dried over magnesiumsulphate and concentrated in vacuo.

Yield: 10.4 g (65.1% of theory)

¹ H-NMR (CDCl₃): δ=0.60 (m, 4H); 0.95 (m, 4H); 1.23 (t, 6H); 2.72 (m,2H); 4.12 (m, 4H); 5.02 (s, 1H); 5.40 (s, 1H); 6.88 (m, 2H); 7.20 (m,2H) ppm.

Example 45 2,6-Dicyclopropyl-4-(4-fluorophenyl)-3,5-di-(methylerythro-(E)-3,5-dihydroxy-hept-6-enoat-7-yl)-pyridine ##STR78##

Example 45 was prepared from the compound from Example 44, in analogy tothe reactions of Examples 3, 27, 5, 6, 7 and 8.

¹ H-NMR (CDCl₃): δ=0.85 (m, 4H); 1.08 (m, 4H); 1.20-1.60 (m, 4H); 2.20(m, 2H); 2.43 (m, 4H); 3.70 (s, 6H); 4.12 (m, 2H); 4.33 (m, 2H); 5.52(dd, 2H); 6.30 (d, 2H); 7.0 (m, 4H) ppm.

Example 46(E/Z)-4-Carboxyethyl-5-(4-fluoro-3-phenoxyphenyl)-2-methyl-pent-4-en-3-one##STR79##

49 g (0.31 mol) of ethyl isobutanoylacetate and 67 g (0.31 mol) of3-phenoxy-4-fluorobenzaldehyde are initially introduced in 300 ml ofisopropanol and a mixture of 1.81 ml (18 mmol) of piperidine and 1.06 ml(18.6 mmol) of acetic acid in 30 ml of isopropanol is added. The mixtureis stirred overnight at room temperature, concentrated in vacuo anddried in a high vacuum. Yield: 110 g (was employed without furtherpurification in Example 47).

Example 47 Diethyl1,4-dihydro-2,6-diisopropyl-4-(4-fluoro-3-phenoxyphenyl)-pyridine-3,5-dicarboxylate##STR80##

30 g (84.3 mmol) of the compound from Example 46 and 13.2 g (84.3 mmol)of ethyl 3-amino-4-methyl-pent-2-enoate are boiled to reflux overnightin 150 ml of ethanol. The mixture is cooled to 0° C., and the depositedprecipitate is filtered off with suction, washed with petroleum etherand dried in a desiccator.

Yield: 18.4 g (44.2% of theory)

¹ H-NMR (CDCl₃): δ=1.05-1.25 (m, 18H); 4.05-4.2 (m, 6H); 4.95 (s, 1H);6.03 (s, 1H); 6.85-7.1 (m, 6H); 7.3 (m, 2H).

Example 48 2,6-Diisopropyl-4-(4-fluoro-3-phenoxyphenyl)-3,5-di(methylerythro-(E)-3,5-dihydroxy-hept-6-enoat-7-yl)pyridine ##STR81##

Example 48 was prepared from the compound from Example 47, in analogy tothe reactions of Examples 3, 27, 5, 6, 7 and 8.

Example 49 (E/Z)-2-Carboxyethyl-1-(4-fluorophenyl)-3-phenyl-propen-3-one##STR82##

38.4 g (0.2 mol) of ethyl benzoylacetate and 24.8 g (0.2 mol) of4-fluorobenzaldehyde are dissolved in 200 ml of toluene, 3 ml ofpiperidine and 3.5 ml of glacial acetic acid are added and the mixtureis heated under reflux overnight in a water separator. After cooling toroom temperature, the mixture is extracted using saturated sodiumhydrogen carbonate solution and water, and the organic phase is driedover magnesium sulphate and concentrated in vacuo. The unreactedstarting materials are removed by distillation in a high vacuum and 55.9g (93% of theory) of crude product are obtained in the distillationresidue.

¹ H-NMR (CDCl₃): δ=1.15 (t, 3H); 4.21 (q, 2H); 6.85-7.95 (m, 10H) ppm.

Example 50 Diethyl1,4-dihydro-4-(4-fluorophenyl)-2-isopropyl-6-phenyl-pyridine-3,5-dicarboxylate##STR83##

29.8 g (0.1 mol) of the compound from Example 49 and 15.7 g (0.1 mol) ofethyl 3-amino-4-methyl-pent-2-enoate are dissolved in 150 ml of ethyleneglycol and boiled to reflux overnight. After concentrating in vacuo, theresidue is dissolved in ethyl acetate, washed once each with 10%strength hydrochloric acid, saturated sodium hydrogen carbonate solutionand water, dried over magnesium sulphate and concentrated in vacuo. Theresidue is chromatographed on a column (silica gel 70-230 mesh, usingethyl acetate/petroleum ether 1:5).

Yield: 8.6 g (19.7% of theory)

¹ H-NMR (CDCl₃): δ=0.85 (t, 3H); 1.20 (m, 9H); 3.85 (q, 2H); 4.12 (q,2H); 4.25 (m, 1H); 5.09 (m, 1H); 5.93 (m, 1H); 6.93 (m, 2H); 7.25-7.50(m, 7H) ppm.

Example 51 4-(4-Fluorophenyl)-2-isopropyl-6-phenyl-3,5-di-(methylerythro-(E)-3,5-dihydroxy-hept-6-enoat-7-yl)-pyridine ##STR84##

Example 51 was prepared from the compound from Example 50, in analogy tothe reactions of Examples 3, 27, 5, 6, 7 and 8.

Example 52(E/Z)-2-(Carboxy-2-cyanoethyl)-3-cyclohexyl-1-(4-fluorophenyl)-propen-3-one##STR85##

66.9 g (0.3 mol) of 2-cyanoethyl cyclohexylcarbonylacetate and 37.2 g(0.3 mol) of 4-fluorobenzaldehyde were reacted analogously to Example49. Yield: 56.7 g (57.4% of theory)

Example 53 3-Cyanoethyl 5-ethyl1,4-dihydro-2-cyclohexyl-4-(4-fluorophenyl)-6-isopropyl-pyridine-3,5-dicarboxylate##STR86##

32.9 g (0.1 mol) of the compound from Example 52 and 15.7 g (0.1 mol) ofethyl 3-amino-4-methyl-pent-2-enoate are dissolved in 100 ml of ethanoland boiled to reflux overnight. After concentrating in vacuo, theresidue is dissolved in ethyl acetate and washed once each with 10%strength hydrochloric acid, saturated sodium hydrogen carbonate solutionand water, the organic phase is dried over magnesium sulphate andconcentrated in vacuo. The residue is chromatographed on a column(silica gel 70-230 mesh, using dichloromethane).

Yield: 7.8 g (17.6% of theory)

Example 54 3-Cyanoethyl 5-ethyl2-cyclohexyl-4-(4-fluorophenyl)-6-isopropyl-pyridine-3,5-dicarboxylate##STR87##

3.53 g (7.55 mmol) of the compound from Example 53 are reactedanalogously to Example 3.

Yield: 2.96 g (84% of theory)

¹ H-NMR (CDCl₃): δ=0.98 (t, 3H); 1.33 (m, 10H); 1.82 (m, 6H); 2.35 (t,2H); 2.69 (m, 1H); 3.10 (m, 1H); 4.02 (q, 2H); 4.15 (t, 2H); 7.08 (m,2H); 7.28 (m, 2H) ppm.

Example 552-Cyclohexyl-3,5-dihydroxymethyl-4-(4-fluorophenyl)-6-isopropyl-pyridine##STR88##

35.7 ml (53.5 mmol) of a 1.5 molar solution of diisobutylaluminumhydride in toluene are added at -78° C. under a nitrogen atmosphere to2.5 g (5.35 mmol) of the compound from Example 54 dissolved in 50 ml ofdry toluene, and the mixture is stirred for 1 hour at -78° C. andovernight at room temperature. 20% strength potassium hydroxide solutionis added to the mixture with ice-cooling and it is extracted severaltimes using toluene.

The organic phase is washed with water, dried over magnesium sulphateand concentrated in vacuo.

Yield: 1.64 g (86% of theory)

¹ H-NMR (CDCl₃): δ=1.20-1.50 (m, 4H); 1.35 (d, 6H); 1.70-1.95 (m, 6H);3.05 (m, 1H); 3.43 (m, 1H); 4.35 (s, 4H); 7.05-7.25 (m, 4H) ppm.

Example 56 2-Cyclohexyl-4-(4-fluorophenyl)-6-isopropyl-3,5-di(methylerythro-(E)-3,5-dihydroxy-hept-6-enoat-7-yl)-pyridine ##STR89##

Example 56 was prepared from the compound from Example 55, in analogy tothe reactions of Examples 5, 6, 7 and 8.

¹ H-NMR (CDCl₃): δ=1.20-1.85 (m, 20H); 2.41 (m, 4H); 2.90 (m, 1H); 3.28(m, 1H); 3.70 (s, 6H); 4.08 (m, 2H); 4.30 (m, 2H); 5.25 (dd, 2H); 6.30(dd, 2H); 7.0 (m, 4H) ppm.

Example 57 (E(2)-3-Ethoxycarbonyl-1-(furane-2-yl)-4-methyl-penten-3-on##STR90##

The compound is prepared analogously to Example 1 fromfurane-2-carbaldehyde.

Yield: 93 % of theory

B.p. 0.5 mbar: 130° C.

Example 584-(Furan-2-yl)-[3,5-bis-3,5-dihydroxy-6-methoxycarbonyl-hex-1-enyl]-2,6-diisopropyl-pyridine##STR91## Example 58 was prepared from the compound from Example 57 inanalogy to the reactions of Examples 2, 3, 55, 5, 6, 7 and 8.

Colorless crystals of m.p. 106° C.

¹ H-NMR (CDCl₃):δ=1.25 (m, 12H); 1.4-1.65 (m,4H); 2.45 (m, 4H); 2.77 (d,2H); 3.3 (m, 2H); 3.6 (m, 2H); 3.6 (d, 2H); 3.72 (s, 6H); 4.1 (m, 2H);4.4 (m, 2H); 5.4 (dd, 2H); 6.12 (m, 1H); 6.4 (m, 1H); 6.5 (d, 2H); 7.45(M, 1H).

Example 59 (E(2)-3-Ethoxycarbonyl-4-methyl-1(thiophen-2-yl)penten-3-on##STR92##

Example 59 was prepared analogously to Example 1 fromthiophene-2-carbaldehyde.

Yield: 86 % of theory

B.p. 1.5 mbar: 145° C.

Example 60 3,5-Bis-(3,5-dihydroxy-6-methoxycarbonyl-hex-1-enyl)-2,6diisopropyl-4-(thiophene-2-yl)-pyridine ##STR93##

Example 60 was prepared from the compound of Example 59 in analogy tothe reactions of Examples 2, 3, 27, 5, 6, 7 and 8.

Colorless crystals of m.p. 62° C.

¹ H-NMR (CDCl₃): δ=1.25 (m, 12H); 1.35-1.6 (m, 4H); 2.45 (m, 4H); 2.6(s, 2H); 3.3 (m, 2H); 3.5 (d, 2H); 3.72 (s, 6H); 4.1 (m, 2H); 4.35 (m,2H); 5.48 (dd, 2H); 6.4 (d, 2H); 6.74 (m, 1H); 6.98 (m, 1H); 7.28 (m,1H).

Example 61 Di-sodium2,6-diisopropyl-4-phenyl-3,5-di-(erythro-(E)-3,5-dihydroxy-hept-6-enoat-7-yl)-pyridine##STR94##

583 mg (1 mmol) of the compound from Example 16 are dissolved in 10 mlof tetrahydrofuran. After addition of 20 ml of 0.1 N NaOH, the mixtureis allowed to stand for 1 hour at room temperature is concentrated invacuo, and the aqueous solution is then lyophilized. Yield: 605 mg(96.5% of theory).

Use Example Example 62

The determination of enzyme activity was carried out as modified by G.C. Ness et al., Archives of Biochemistry and Biophysics 197, 493-499(1979). Male Rico rats (body weight 300-400 g) were treated for 11 dayswith altromin powdered food, to which 40 g of cholestyramine/kg of foodwas added. After decapitation, the liver of the animals was taken outand placed on ice. The livers were comminuted and homogenized 3 times ina Potter-Elvejem homogenizer in 3 volumes of 0.1 M saccharose, 0.05MKCl, 0.04M K_(x) H_(y) phosphate, 0.03M ethylenediaminetetraacetic acidand 0.002M dithiothreitol (SPE) buffer pH 7.2. The homogenizate wassubsequently centrifuged for 15 minutes at 15,000^(*) g and the sedimentwas discarded. The supernatant was sedimented at 100,000 g for 75minutes. The pellet was taken up in 1/4 volumes of SPE-buffer,homogenized again and subsequently centrifuged again at 100,000 g for 60minutes. The pellet was taken up in 5 times its volume of SPE-buffer,homogenized, and frozen and stored at -78° C. (=enzyme solution).

For testing, the test compounds (or mevinolin as a reference substance)were dissolved in dimethylformamide with the addition of 5% by volume of1N NaOH and employed in the enzyme test using 10 μin variousconcentrations. The test was started after 20 minutes preincubation ofthe compounds with the enzyme at 37° C. The test batch was 0.380 ml andcontained 4 μmol of glucose-6-phosphate, 1.1 mg of bovine serum albumin,2.1 μmol of dithiothreitol, 0.35 μmol of NADP, 1 unit ofglucose-6-phosphate dehydrogenase, 35 μmol of K_(x) H_(y) phosphate pH7.2, 20 μl of enzyme preparation and 56 nmol of3-hydroxy-3-methyl-glutaryl coenzyme A (glutaryl-3-¹⁴ C) 100,000 dpm.

The batch was incubated for 60 minutes at 37° C. and the reaction wasstopped by addition of 300 μl of 0.24 m HCl. After a post-incubation of60 minutes at 37° C., the batch was centrifuged and 600 μl of thesupernatant were applied to a 0.7×4 cm column filled with Biorex.sup.(R)5-chloride 100-200 mesh (anion exchanger). This was washed with 2 ml ofdistilled water, and 3 ml of aquasol was added to the eluent pluswashing water and counted in the LKB scintillation counter. IC₅₀ valueswere determined by intrapolation by plotting the percentage inhibitionagainst the concentration of the compound in the test. To determine therelative inhibitory potency, the IC₅₀ value of the reference substancemevinolin was set at 100 and compared with the simultaneously determinedIC₅₀ value of the test compound.

Example 63

The subchronic action of the disubstituted pyridines on bloodcholesterol values of dogs was tested in feeding experiments extendingover several weeks. For this, the substance to be investigated was givenp.o. once daily in a capsule to healthy beagle dogs together with thefeed over a time period of several weeks. In addition, during the entireexperimental period, i.e. before, during and after the administrationperiod, the substance cholestyramine (4 g/100 g of feed) to beinvestigated was mixed with the feed as the gallic acid sequestrant.Twice weekly, venous blood was taken from the dogs and the serumcholesterol was determined enzymatically. The serum cholesterol valuesduring the administration period were compared with the serumcholesterol values before the administration period (controls).

A lowering of the serum cholesterol of about 22.4% thus resulted, e.g.,for the Na salt of Example 8 (2,6-diisopropyl4-(4-fluorophenyl)-3,5-di-(sodiumerythro-(E)-3,5-dihydroxy-hept-6-enoat-7-yl)-pyridine) after a 2-weekadministration of 8 mg/kg p.o. daily.

It will be appreciated that the instant specification and claims are setforth by way of illustration and not limitation, and that variousmodifications and changes may be made without departing from the spiritand scope of the present invention.

What is claimed is:
 1. A compound of the formula ##STR95## in which Qstands for F, lower alkyl or phenoxy,n stands for 1 or 2, R² stands forC₁ -C₆ alkyl, C₃ -C₈ cycloalkyl, phenyl or benzyl, R³ stands for C₁ -C₆alkyl or C₃ -C₈ cycloalkyl, and R⁷ stands for hydrogen, C₁ -C₆ alkyl oran alkali metal cation,and the stereoisomeric forms which can have the Eor Z configuration thereof.
 2. A compound according to claim 1 in whichQ_(n) is 4-F.
 3. A compound according to claim 1, wherein such compoundis 2,6-diisopropyl-4-(4-fluorophenyl)-3,5-di)-methyl3,5-dihydroxy-hept-6-enoat-7-yl)-pyridine of the formula ##STR96##
 4. Acomposition for the treatment of lipoproteinaemia and arteriosclerosiswhich comprises an amount effective therefor of a compound according toclaim 1 and a pharmaceutically acceptable diluent.
 5. A method oftreating lipoproteinaemia and arteriosclerosis which comprisesadministering to a patient in need thereof an amount effective thereforof a compound according to claim
 1. 6. The method according to claim 5,wherein such compound is2,6-diisopropyl-4-(4-fluorophenyl)-3,5-di-(methyl3,5-dihydroxy-hept-6-enoat-7-yl)-pyridine.